The overall goals of this project are to define the common molecular mechanisms in the pathogenesis of biliary cirrhosis. Biliary cirrhosis accounts for approximately 20% of cases liver failure in adults and more than 50% of cases of liver failure in children, yet its pathogenesis has only recently been examined in a systematic fashion. The pathologic hallmarks of biliary cirrhosis are disordered bile ductular proliferation and bridging fibrosis originating from portal tracts. The two cell types instrumental to these processes are bile duct epithelia (BDE) and portal fibroblasts (PF). BDE are highly dynamic cells that adapt to local stimuli, and PF, like hepatic stellate cells (HSC), undergo myofibroblastic differentiation into matrix-producing cells in response to injury. Our recent studies demonstrate that BDE and PF signal to each other in an intercellular fashion, forming a crosstalk signaling loop. BDE signal to PF via release of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), whereas PF signal to BDE via regulated expression of ecto-nucleoside triphosphate diphosphohydrolase-2 (NTPD2). The hypothesis of this application is that biliary cirrhosis is mediated by dysregulation of this crosstalk loop. This hypothesis will be tested via three specific aims: Aim 1. Define steps leading to biliary cirrhosis at the level of BDE. This aim will identify mechanisms regulating MCP-1 and IL-6 release by BDE. Aim 2. Define steps leading to biliary cirrhosis at the level of PF. This aim will define signal transduction mechanisms and downstream effects of MCP-1 and IL-6 in PF. Aim 3. Determine the pathophysiological importance of proposed causes of biliary cirrhosis in biologically relevant models. This aim will determine whether targets identified in Aims 1 &2 are dysregulated in biliary cirrhosis. We believe that the proposed research will generate new paradigms in the understanding of biliary cirrhosis and will ultimately lead to new approaches to the prevention and/or treatment of this critically important condition.